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Consequences of Telomere Dysfunction in Cancer and Aging

Research Summary

Using complementary research programs in fission yeast and zebrafish, Miguel Godinho Ferreira investigates the events initiated by telomere shortening, from the cellular level to the organism level, and how these contribute to cancer and aging. He is also interested in how chromosome rearrangements contribute to evolutionary processes, such as speciation.

The strongest risk factor for cancer is age, with 75 percent of cases diagnosed in people aged 60 years and older. Thanks largely to our ever-increasing knowledge of tumor formation, emergent therapies have improved our ability to fight cancer. Our challenge now lies in understanding the molecular mechanisms responsible for aging so that we can identify new ways to reduce the lifetime risk for cancer (and other age-associated diseases), leading to a prolonged, healthier life.

Telomeres, the natural ends of chromosomes in eukaryotes, have unique properties that distinguish them from DNA ends that are damaged. Most human somatic cells lack telomerase, the enzyme that generates telomeres. Continuous proliferation of cells lacking telomerase leads to telomere depletion and ultimately to telomere loss. When telomere function is lost, chromosome ends are treated as deleterious DNA double-strand breaks that usually result in cell death. If, however, these cells survive, chromosomes will be joined by their ends, yielding dicentric entities that can break upon mitosis. This so-called break–fusion–bridge cycle is responsible for unequal distribution of genetic information to daughter cells as well as the formation of new, unprotected ends. The ensuing genetic disarray is thought to be the major contributor to genomic instability—a characteristic that most cancers share. This idea is at the heart of our current model for tumorigenesis and is the basis for the causal association between aging and cancer.

Our goal is to investigate the mechanisms underlying chromosome-end protection and the outcomes of its failure, from the cellular level to the organism level. Our work will enable the discovery of key regulators guarding cells from genomic instability. Ultimately, we aim to prevent the incidence of cancer associated with aging. We plan to achieve this goal by identifying and manipulating the agents responsible for this association.

Short Telomeres as a Cause ofCancer and Aging
From an early stage of my career, I felt the necessity to integrate our molecular knowledge in the context of the whole organism. Despite all the crucial work performed in the mouse model system, the major disparities in telomere length between humans and mice deterred me from using this system (mouse telomeres are 5–10 times longer than those of humans). The telomerase-deficient mouse showed no relevant phenotypic differences from its normal siblings, suggesting that—at least for laboratory mouse strains—telomere length could not regulate cell proliferation or aging.

To analyze the consequences of telomere dysfunction in the whole organism, I have chosen to work with zebrafish, an organism with naturally shorter telomeres. My goal is to use the knowledge acquired on the molecular nature of telomere protection to understand the consequences of its failure at the organism level. Our base hypothesis implies that telomere dysfunction signals a cascade of events that triggers cellular senescence and organism aging. I plan to test this idea by manipulating telomere dysfunction (in a time- and tissue-specific manner), using transgenic zebrafish. My vision is that enabling timely telomere protection in a few key tissues will postpone aging in the whole organism and, as a consequence, reduce the frequency of age-associated diseases, namely, cancer.

We have two main projects running in our lab. The first concerns the broader question of whether telomere defects are cell-autonomous or, alternatively, whether telomere dysfunction acquired in specific tissues somehow signals other organs, thereby coordinating organism aging. The second question relies on a more straightforward use of telomerase-mutant zebrafish to genetically determine the stage at which telomerase expression is required during cancer development, using an established model of invasive melanoma.

Molecular Mechanism of Telomere Checkpoint Inhibition
As the natural ends of chromosomes, telomeres are distinct from deleterious DNA double-strand breaks. Even though DNA repair and checkpoints do not normally occur at telomeres, upon replication fork passage at the end of S phase, both ATM and ATR are activated without any interference in cell cycle progression. In my lab, using fission yeast we showed that checkpoint activation at telomeres does not lead to cell cycle arrest, even though ATM and ATR are activated and DNA repair is ongoing. I have proposed a model whereby telomeres normally initiate checkpoints at every S phase, but signaling is interrupted because of local chromatin status.

The major focus of this project is the existence of "chromatin privileged" locations on the chromosome that restrict checkpoints from blocking cell cycle progression. We are addressing the following questions: What constitutes a chromatin-privileged region? What mechanisms establish and maintain these environments? Are other locations, apart from telomeres, under similar regulation?

Chromosome Rearrangements as the Basis for Evolutionary Adaptation and Speciation
As a consequence of telomere deprotection, chromosomes may undergo break–fusion–bridge cycles, resulting in gross chromosomal rearrangements (GCRs). Even if most of these events are deleterious, several cells survive when telomere function is restored. GCRs account for the chromosome instability observed in most human cancers. As with cancer cells, we propose that GCRs, when not lethal, may be adaptive and even beneficial. In whole organisms, they may be behind reproductive isolation in evolutionary processes, such as speciation. To test this hypothesis, we generated 10 GCR-containing fission yeast strains (two inversions and eight translocations) by using an established Cre-loxP system. These GCRs are the only difference from the parental strain. As expected, we observed reduced viability of offspring in hybrid crosses. Using direct competition assays, we showed that chromosome structure is an adaptive trait that, depending on the environment, may select for different chromosome variants. We have devised an evolution experiment to test whether GCRs are capable of leading to further genetic isolation, if they are allowed to reproduce with the nonrearranged counterpart.